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Mechanism of neuroprotection in stroke-related models
Title
Mechanism of neuroprotection in stroke-related models.
Creator
Pan, Chunliu., Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
Stroke is the third leading cause of mortality in the United States, and so far, no clinical interventions have been proved truly effective in stroke treatment. Stroke my result in hypoxia, glutamate release and oxidative stress, etc. The purpose of this dissertation study is to evaluate the neuroprotective effects of four drugs (taurine, G-CSF sulindac and DETC-MeSO) on PC12 cell line or primary cortical neuronal cell culture, and to understand the protective mechanisms underlying in three...
Show moreStroke is the third leading cause of mortality in the United States, and so far, no clinical interventions have been proved truly effective in stroke treatment. Stroke my result in hypoxia, glutamate release and oxidative stress, etc. The purpose of this dissertation study is to evaluate the neuroprotective effects of four drugs (taurine, G-CSF sulindac and DETC-MeSO) on PC12 cell line or primary cortical neuronal cell culture, and to understand the protective mechanisms underlying in three stroke-related models : hypoxia, excessive glutamtate and oxidative stress. In the first part of this dissertation, we studied the neuroprotection of taurine against oxidative stress induced by H2O2 in PC12 cells. Our results show that extracellular taurine exerts a neuroprotective function by restoring the expression of Bcl-2 and downregulation of the three Endoplasmic Reticulum (ER) stress markers : GRP78, Bim and CHOP/GADD153, suggesting that ER stress can be provoked by oxidative stress and can be suppressed by taurine. In the second part, glutamate excitotoxicity-induced ER stress was studied with dose and time as variables in primary cortical neurons. The results demonstrate that glutamate excitotoxicity leads to the activation of three ER stress pathways (PERK, ATF6 and IRE1) by initiating PERK first, ATF6 second and IRE1 pathway last. The third part of this dissertation studied the robust and beneficial protection of taurine in cortical neurons under hypoxia/reoxygenation or glutamate toxicity condition. We found that taurine suppresses the up-regulation of GRP778, Bim, caspase-12 and GADD153/CHOP induced by excessive glutamate or hypoxia/reoxygenation, suggesting that taurine may exert a protective function against hypoxia/regeneration by reducing the ER stress., Moreover, taurine can down-regulate the ratio of cleaved ATF6 and full length ATF6, and p-IRE1 expresssion, indicating that taurine inhibits the ER stress induced by hypoxia/reoxygenation or glutamate through suppressing ATF6 and IRE1 pathways. In the fourth part, the synergistic benefits of the combination of taurine and G-CSF, and the neuroprotective effects of G-CSF, sulindac or DETC-MeSO are studied in cortical neurons. Our results show that G-CSF, sulindac or DETC-MeSO can highly increase the neuron visibility by inhibiting ER stress induced by hypoxia/reoxygenation or glutamate toxicity. Furthermore, we proved that G-CSF or sulindac can significantly inhibit the activation of ATF6 or IRE1 pathway stimulated by hypoxia/reoxygenation, and DETC-MeSO can suppress the activation of both PERK and IRE1 pathways in primary neuron cultures. These findings provide promising and rational strategies for stroke therapy.
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Date Issued
2012
PURL
http://purl.flvc.org/FAU/3352284
Subject Headings
Sulindac, Physiological effect, Taurine, Physiological effect, Cerebral ischemia, Prevention, Biochemical markers, Diagnostic use, Apoptosis, Oxidation reduction reaction
Format
Document (PDF)
Synthesis, structural characterization and biological studies of organotin polyethers (Sn-O)
Title
Synthesis, structural characterization and biological studies of organotin polyethers (Sn-O).
Creator
Barot, Girish Vallabhbhai., Charles E. Schmidt College of Science, Department of Chemistry and Biochemistry
Abstract/Description
Cancer is the second leading cause of death in the western world. In order to treat various types of cancer, platinum-based drugs are most widely employed as metal-containing chemotherapeutic agents. However, their clinical usage is hindered by toxic side effects, and by the emergence of drug resistance. Our focus was to replace platinum with less toxic metal like tin which can give better alternatives for cancer treatment. The major aim of our study was to synthesize novel organotin...
Show moreCancer is the second leading cause of death in the western world. In order to treat various types of cancer, platinum-based drugs are most widely employed as metal-containing chemotherapeutic agents. However, their clinical usage is hindered by toxic side effects, and by the emergence of drug resistance. Our focus was to replace platinum with less toxic metal like tin which can give better alternatives for cancer treatment. The major aim of our study was to synthesize novel organotin polyethers (Sn-O) which can be used to combat cancer. Preliminary results from our laboratory using organotin polyethers, that were synthesized by varying the structure of diols showed growth inhibition in Balb-3T3 cells. This study directly led us to hypothesize the two structural windows, first by changing the distance between diol and second, by presence of unsaturation in diols, the biological activity of organotin polyethers (Sn-O) can be enhanced significantly. Different series of polymeric compounds were synthesized based upon these two structural windows and the formation of products was validated using standard techniques like infrared spectroscopy (IR), light scattering photometer, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and nuclear magnetic resonance (NMR). The synthesized polymers arrested the growth of cancer cell lines including bone, prostate, colon, breast, pancreas and lung cancer derived cell lines in vitro. In number of instances where chemotherapeutic index values of two and greater were found that these polymers are significantly more active against cancer cells than non-cancerous cells in culture., These results support the starting premise that the polymers may exhibit cancer cell selectivity. In general, it was found that the presence of unsaturation increased the probability that the polyether would inhibit the growth of various cancer cell lines. Further, in some cases, polyethers with short distances between the oxygen atoms showed a superior ability to inhibit the growth of various cancer cell lines in comparison to those with longer distances between the oxygen atoms. These results provide a framework for the discovery of novel cancer therapeutics.
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Date Issued
2009
PURL
http://purl.flvc.org/FAU/186672
Subject Headings
Organometallic polymers, Cancer, Molecular aspects, Apoptosis, Molecular aspects, Antineoplastic agents, Testing, Polymers in medicine
Format
Document (PDF)